Submissions for variant NM_206933.4(USH2A):c.14570G>C (p.Gly4857Ala)

gnomAD frequency: 0.00004  dbSNP: rs749889050

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000674387	SCV000799712	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2018-05-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001047727	SCV001211707	likely pathogenic	not provided	2024-03-20	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 4857 of the USH2A protein (p.Gly4857Ala). This variant is present in population databases (rs749889050, gnomAD 0.006%). This missense change has been observed in individual(s) with USH2A-related conditions (PMID: 27460420, 31456290). ClinVar contains an entry for this variant (Variation ID: 558160). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt USH2A protein function with a positive predictive value of 80%. This variant disrupts the p.Gly4857 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been observed in individuals with USH2A-related conditions (PMID: 32188678, 32675063), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271563	SCV002556086	uncertain significance	not specified	2022-06-22	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.14570G>C (p.Gly4857Ala) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250876 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.14570G>C has been reported in the literature as a compound heterozygous genotype in at-least one individual with Usher syndrome who has been subsequently cited by others (example, Bonnet_2016, Fakin_2020) and as a likely pathogenic classification in a non-informative genotype (zygosity/genotype not specified) in a cohort undergoing comprehensive analysis for inherited retinal diseases (IRD) (example, Sharon_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely pathogenic, n=1; VUS, n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV003453383	SCV004183041	uncertain significance	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001829883	SCV004183042	uncertain significance	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003250	SCV001161330	likely pathogenic	Retinitis pigmentosa	2019-06-23	no assertion criteria provided	research
Natera, Inc.	RCV001829883	SCV002088214	uncertain significance	Usher syndrome type 2A	2020-09-14	no assertion criteria provided	clinical testing